The major function of the adrenal gland is to regulate metabolism in the body so that an intermittent intake of food can be regulated to maintain a constant metabolite supply to the cells. This is accomplished by producing steroid hormones which can control the conversion of incoming nutrients, such as aminoacids, glucose and fats into storage depots from which they can thereafter be released or interchanged, allowing a continuous flow of optimum energy and growth factors to the cells.
The steroid hormones are divided mainly into three classes. The first is glucocorticoids (cortisol), also known as gluconeogenic or diabetogenic steroids, which can convert aminoacids into glucose for direct use or store the glucose as glycogen for later use. Cortisol can therefore have an anti-anabolic effect through the depletion of aminoacids needed for protein synthesis and a diabetogenic effect through the direct release of glucose from the glycogen store.
A glucocorticoid excess, resulting from an excess of the pituitary hormone, adrenal corticoid trophic hormone (ACTH), which controls cortisol production, causes Cushing's Syndrome, an uncommon disease. Intake of an excess amount of cortisol from pharmacological use of steroids can also cause Cushing's Syndrome or Cushingoid-like disorders (hypercorticosteroidism, nor more briefly hypercorticoidism) which are progeric in that they resemble the symptoms of the diseases of aging, e.g. obesity, hypertension, diabetes, renal stones, osteoporosis, mental disorder, menstrual disturbance, susceptibility to infection and poor wound healing.
The second category of steroids is known as the adrenal androgens. Dehydroepiandrosterone (DHEA) is the principal representative of this category. The adrenal androgens which have an anabolic action are produced with puberty, reach a peak in early adulthood and then, beyond the age of 50, decline to very low levels. Secretion of ACTH, which also controls corticosteroid production, shows no such age related fluctuation.
The third category of adrenal steroids is the mineralocorticoids (aldosterone) which control the mineral balance of the body and is partially under ACTH control in that ACTH accelerates the conversion of cholesterol to all adrenal steroids.
When the body is subjected to stress, physical or mental, e.g. injury, cold, starvation or threats, real or imagined, ACTH stimulates the adrenal cortex to produce steroids in increased amounts in order to provide the body with resources necessary for response to the stress, storage or release of glucose when needed, lipid deposition or mobilization in order to maintain the energy equilibrium of the body under conditions where extra energy may be needed and/or starvation of the cells becomes a possibility.
Under normal conditions, ACTH stimulates the adrenals to secrete both cortisol and DHEA. In the aging individual, cortisol is stimulated but DHEA is not, thus resulting in relative hypercortisolism.
It is shown in the first of said related applications that DHEA is useful in the treatment of diabetes in mutant mice and treatment of adult-onset diabetes in obese individuals. The genetic form of diabetes in mice is associated with hypercorticosteroidism. Hypercorticosteroid syndromes can occur as a result of excessive ACTH production due either to stress, hypofunction of the adrenal glands, pituitary tumors, ectopic ACTH production or administration of pharmacologic doses of cortisol.
DHEA is metabolized in the body. A major metabolite is etiocholanolone (5-.beta.-androstan-3-.alpha.-ol-17-one, (hereinafter referred to as .alpha.-ET) and in normal individuals it is excreted in amounts of about 0.5 mg/100 ml. .beta.-etiocholanolone (5-.beta.-androstan-3-.beta.-ol-17-one, hereinafter referred to as .beta.-ET), is a minor metabolite in man. Even when large quantities are injected, there is a significant conversion of the 3.alpha. to the 3.beta.-hydroxy compound. Kappas, et al., The Thermogenic Effect and Metabolite Fate of Etiocholanolone in Man, J. Clin. Endrocrin. & Metab., 18, 1043-1055 (1958). In a diabetic individual, the quantity of .alpha.-ET excreted is significantly less than in the normal individual.
.alpha.-ET had been considered to be an inert end product whose sole fate was conjugation and excretion until it was shown that in its free (unconjugated) state, it had highly potent pyrogenic effects when injected intramuscularly in males, less potency in females and none in other species. No febrile reaction results when .alpha.-ET is administered intravenously, or orally, or when .beta.-ET is administered by any route. Kappas, et al., Thermogenic Properties of Steroids, in Methods in Hormone Research, Dorfman Ed. Vol. 4, p. 1 (New York & London Academic Press) (1965).
The spectrum of biological significance for etiocholanolones has been extended to include the regulation of porphyrin and hemesynthesis in hepatic and erythroid cells. Granick et al., Steriod Control of Porphyrin and Hemebiosynthesis, A New Biological Function of Steriod Hormone Metabolites, Proc. Nat. Acad. Sci., 57:1463 (1967). .alpha.-ET as well as other non-pyrogenic 5-.beta. saturated steroids are also inducers of porphyrin synthesis. Wolff, et al., The Biological Properties of Etiocholanolone, Ann. Int. Med., 67, 1268-1295 (1967).
Said copending Application Ser. No. 566,223 describes that the administration of .alpha.-ET. .beta.-ET or mixtures thereof reproduce the effects of DHEA in antagonizing the effects of hypercortisolism. The effective therapeutic amount of these compounds are considerably lower than the dosage of DHEA required for maximum effect in normalizing blood sugar and maintaining islet integrity.
The administration of estrogens also reproduce the effects of DHEA in antagonizing the effects of hypercortisolism when administered at relatively high concentrations. For example, the administration of estradiol (estra-1,3.5(10)-tri-3,17.beta.-diol) at 50 ug. twice per week subcutaneously to chow fed male mice of about 30 grams in weight prevented hyperglycemia and islet atrophy, sustained elevated plasma and pancreatic plasma immunoreactive insulin concentrations and increased the percent granulated beta cells. However, the use of estradiol and other estrogens at such a high concentration of about 5 mg/kg is undesirable because of the estrogenic activity of these materials at such dosages. It has now been surprisingly discovered that when the estrogens are administered in a non-estrogenic effective amount in combination with .alpha.- and/or .beta.-ET, a synergistic effect in antagonizing the effects or hypercortisolism is achieved. The synergistic effect also permits the quantity of .alpha.- and/or .beta.-ET to be reduced from the levels required when these compounds are used in the absence of the estrogen.
It is accordingly the object of this invention to provide a new method for treating diabetes-obesity syndrome and associated hypercorticoidism and enhancing the function or by preventing the destruction of the pancreatic islet beta cells using a synergistic combination .alpha.-ET and/or .beta.-ET and estrogen as antidiabetic and antihyperglycemic agents. This and other objects of the invention will become apparent to those skilled in this art from the following description.